Dr. Tong's long-term goal is to better understand the physiologic functions of the ghrelin system on human insulin secretion and glucose tolerance. The concentration of ghrelin, a hormone secreted from the gut, rises before meals and decreases after eating. It is not only an important signal for meal preparation, but also influences insulin secretion from the pancreas and blood glucose levels. Data collected from previous research suggests that acylated ghrelin (AG) and unacylated ghrelin (UAG), may have opposite effects on glucose metabolism in humans with AG inhibiting insulin secretion and UAG increasing it. However, due to the lack of consistent and sensitive measures of insulin secretion and glucose tolerance, the role of UAG on human glucose metabolism remains poorly understood. Dr. Tong's ongoing K23-funded studies aim to clarify the physiologic role of AG on regulating 2-cell function and begin to understand the mechanism by which this occurs. Preliminary data from Dr. Tong's K23 studies indicate that AG decreases intravenous (IV) glucose-stimulated insulin secretion in healthy, lean individuals. The research proposed in this application is a logical extension of the K23 project and aims to test the central hypothesis that UAG administration in healthy individuals will enhance insulin secretion and improve glucose tolerance. Dr.Tong also hypothesizes that an antagonistic relationship exists between UAG and AG, such that the effects of UAG will be blunted by co- administration of AG. Towards this aim, Dr. Tong plans to administer synthetic human AG, UAG, combined AG and UAG, and saline (control) via IV infusion to healthy individuals on four separate days. Acute phase insulin release, peripheral insulin sensitivity, and glucose tolerance will be measured using a sensitive and robust method, the frequently sampled IV glucose tolerance test. This proposed work will provide definitive results that are critical for the understanding of the role of ghrelin in human glucose metabolism. Moreover, this project will provide important new insights as to whether the ghrelin system is involved in the pathogenesis of type-2 diabetes and whether it might be utilized in treating diabetic patients. Addition of this project to the studies described in Dr. Tong's K23 will allow the development of a more complete picture of the role of ghrelin in glucose metabolism, and generate more refined hypotheses for advancing this important area through future studies. PUBLIC HEALTH RELEVANCE: The gut hormone ghrelin is known to be important for the regulation of food intake and energy balance but the specific role its two molecular forms, acylated and unacylated ghrelin, in glucose homeostasis is less well defined. The goal of this project is to clarify whether unacylated ghrelin has not only an independent effect on insulin secretion and glucose tolerance but also counterbalancing actions with respect to acylated ghrelin in healthy human subjects. The knowledge to be gained from this proposed research will be significant both in advancing our understanding of the role of the ghrelin system in human glucose metabolism and in generating a foundation for the development of novel ghrelin-based therapy for the treatment of metabolic diseases.